Pharmacological Treatment of Dysrhythmias

Question 1

Describe the Vaughan Williams classification of anti-dysrhythmic drugs.

Answer 1

• 1a: -Sodium channel blockers, disopyramide
• 1b: -Sodium channel blockers, lignocaine
• 1c: -Sodium channel blockers, flecainide
• 2: -b-adrenoreceptor blockers, sotalol
• 3: -Potassium channel block, amiodarone
• 4: -Calcium channel blockers, verapamil
• Unclassified: adenosine and digoxin

where: 
Class 1 = Sodium Channel Blockers
Class 2 = Beta Blockers
Class 3 = Potassium Channel Blockers
Class 4 = Calcium Channel
Blockers

Question 2

Explain the mechanism of action of Class I anti-dysrhythmic drugs.

Answer 2

• Inhibit action potential propagation and reduce the rate of cardiac depolarisation during phase 0.
• Depolarisation switches channels from resting to open states- known as activation. Maintained depolarisation causes the channels to move to a refractory state - known as inactivation. Cardiac myocytes must repolarise to reset the sodium channels back to resting state.
• These drugs bind to the open and refractory states of voltage gated Sodium channels (from the intracellular side of the channel) and so are viewed as use-dependent i.e. work more effectively if there is high activity and so are more effective against abnormal high frequency activity and not so much against normal beating rates.

Question 3

What is the difference between class Ia, Ib, and Ic ?

Answer 3

Subdivision to class a, b and c is based on the properties of the drugs in binding to sodium channels in their various states such as open, refractory and resting.

Question 4

Where on the channels do class I anti-dysrhythmic drugs bind ?

Answer 4

On the drug binding domains of voltage-gated sodium channels.

Question 5

Give an example of class I anti-dysrhythmic drugs.

Answer 5

1a: disopyramide
1b: lignocaine
1c: flecainide

Question 6

Describe some clinical uses of class I anti-dysrhythmic drugs.

Answer 6

Class 1a. Disopyramide (resembles quinidine)
• Ventricular dysrhythmias, prevention of recurrent atrial fibrillation triggered by vagal over activity.

Class 1b. Lignocaine (given by IV)
• Treatment and prevention of ventricular tachycardia and fibrillation during and immediately after MI.

Class 1c. Flecainide
• Suppresses ventricular ectopic beats. Prevents paroxysmal atrial fibrillation and recurrent tachycardias associated with abnormal conducting pathways.

Question 7

Explain the mechanism of action of Class 2 anti-dysrhythmic drugs.

Answer 7

• Block b-1 receptors slow the heart and decrease cardiac output.
• b-1 receptor activation increases the rate of depolarisation of the pacemaker cells so blocking them decreases this.
• b-1 receptor activation enhances calcium entry in phase 2 of the cardiac action potential so blocking them reduces this.
• b-blockers increase the refractory period of the AV node so prevent recurrent attacks of supraventricular tachycardias.
• Basically increased sympathetic drive and influence tend to promote dysrhythmias and so attenuating their influence will slow the heart and decrease their occurrence.

Question 8

Give an example of class 2 anti-dysrhythmic drugs.

Answer 8

Sotalol, bisoprolol, atenolol

Question 9

Describe some clinical uses of class 2 anti-dysrhythmic drugs.

Answer 9

Sotalol, bisoprolol, atenolol. Clinical uses are to reduce mortality following MI and to prevent recurrence of tachycardias provoked by increased sympathetic activity.

Question 10

Explain the signal transduction pathway of β adrenoceptors, and hence explain how beta blockers have an effect on dysrythmias.

Answer 10

Beta adrenoreceptor is a G protein coupled receptor. The stimualtory Gs protein it is coupled with can increase activity of effector molecule (Adenylate Cyclate). AC can in turn increase production of cAMP, which is a substrate for the enzyme PKA. PKA causes phosphorylation of calcium channels, which results in their increased activity. By blocking this pathway using beta blockers, we are effectively decreasing the activity
of calcium channels, which is especially important for nodal tissue where calcium is the ion driving the depolarisation (rather than sodium).

Question 11

Explain the mechanism of action of Class 3 anti-dysrhythmic drugs.

Answer 11

• prolongs the cardiac action potential by prolonging the refractory period (delays repolarisation by blocking potassium channels)
• Drug gets from extracellular space to cytosol, at which point the activation gate opens, and the drug enters the vestibule. Closing of the gate traps the drug. Channel inactivation stabilizes drug binding.

Question 12

Give examples of Class 3 anti-dysrhythmic drugs.

Answer 12

• Amiodarone, tachycardia associated with the Wolff- Parkinson-White syndrome. The combination of Wolff-Parkinson-White syndrome and atrial fibrillation can be life-threatening.
• Amiodarone is also effective in many other supreventricular and ventricular tachyarrhythmias.
• Sotalol combines class 3 with class 2 actions. It is used in supraventricular dysrhythmias and suppresses ventricular ectopic beats and short runs of ventricular tachycardia.

Question 13

Define Wolff-Parkinson-White Syndrome.

Answer 13

Wolff-Parkinson-White syndrome is a heart condition featuring episodes of an abnormally fast heart rate. Episodes can last for seconds, minutes, hours or (in rare cases) days. They may occur regularly, once or twice a week, or just once in a while.

Question 14

Describe the mechanism of action of Class 4 drugs.

Answer 14

• Blocks cardiac voltage- gated L-type calcium channels.
• Slow conduction through the SA and AV nodes where the conduction of the AP relies on the slow calcium currents.
• They shorten the plateau of the cardiac AP and reduce the force of contraction of the heart.

Question 15

Give examples of Class 4 drugs.

Answer 15

Verapamil and diltiazem.

Question 16

Illustrate, in graphical fashion, the effect of a class 3 drug on a ventricular AP.

Answer 16

Refer to slide page 15 in lecture on “Pharmacological Treatment of Dysrhythmias”

Question 17

Illustrate, in graphical fashion, the effect of a class 4 drug on a ventricular AP.

Answer 17

Refer to slide page 17 in lecture on “Pharmacological Treatment of Dysrhythmias”

Question 18

Describe the clinical uses of class 4 drugs.

Answer 18

• Verapamil is used to prevent recurrence of supraventricular tachycardias (SVTs) + to reduce the ventricular rate in patients with atrial fibrillation provided they do not have Wolff-Parkinson-White syndrome BUT IT IS INEFFECTIVE AND DANGEROUS in ventricular dysrhythmias.
• Diltiazem is similar to verapamil but has more effect on smooth muscle calcium channels and has less bradychardia.

Question 19

Identify the main phases of a cardiac AP.

Answer 19

Phase 0: Rapid depolarisation
Phase 1: Partial repolarisation
Phase 2: Plateau 
Phase 3: Repolarisation
Phase 4: Pacemaker potential

Question 20

What ions drive the different phases of a cardiac AP ?

Answer 20

Phase 0- Sodium channels
Phase 1- Potassium channels
Phase 2- Calcium channels (and Potassium channels)
Phase 3- Potassium channels
Phase 4- Potassium channels

Question 21

Will the AP profile be the same depending on where along the conduction pathway you are taking the measurement from ?

Answer 21

No, AP profile is different dependent on which part of the conduction pathway you are looking at.

Question 22

Briefly state where each class of anti-dysrhythmic drug will act along the cardiac AP.

Answer 22

Class 1: (decreases) Phase 0
Class 2: (decrease) phases 2 and (decreases slope of) phase 4
Class 3 (and 1a): (decreases) Phase 3
Class 4: (decreases) Phase 2

Question 23

Identify two unclassified anti-dysrhythmic drugs.

Answer 23

Adenosine and Digoxin

Question 24

Describe the mechanism of action of Adenosine.

Answer 24

• Adenosine outside the cell binds to A1 receptor (receptor responsible for the effect on the AV node). A1 receptor is coupled with Gi (inhibitory) and Go (other) proteins. Upon adenosine binding, the Gi protein will result in inhibition of Adenylate Cyclase which will in turn reduce production of cAMP. This will in turn reduce phosphorylation and thereby activity of Calcium channels. Since these channels drive depolarisation of nodal tissue, blocking them will slow the pacemaker potential down.
• These receptors are linked to the same cardiac potassium channels that are activated by ACh. and so it hyperpolarises cardiac conducting tissue (by opening Potassium channels) and slows the heart rate. It decreases pacemaker activity.

Question 25

Where is adenosine produced ? What does it act on ?

Answer 25

Produced endogenously with effects on breathing, cardiac and smooth muscle, vagal afferent nerves and platelets.

Question 26

Describe the clinical uses of adenosine.

Answer 26

Used to terminate SVTs.

Question 27

Where is digoxin derived from ?

Answer 27

Cardiac glycosides are a family of compounds that are derived from the foxglove plant (Digitalis purpurea)

Question 28

Describe the mechanism of action of digoxin.

Answer 28

• Increase vagal efferent activity to the heart (by unknown mechansim)
• This parasympathomimetic action of digoxin reduces sinoatrial firing rate (decreases heart rate) and reduces conduction velocity of electrical impulses through the atrioventricular node

Question 29

What are the risks of digoxin when given at toxic concentrations ?

Answer 29

• Toxic concentrations disturb sinus rhythm. Inhibition of Na+/K+ pump cause depolarisation – ectopic beats. Because:

-During coupling, cardiac AP
is converted into mechanical stimulus.
-This is driven by Calcium (released from stores, binds to contractile machinery, muscle contracts)
-In relaxation, need to deplete calcium stores so calcium can be taken back into sarcoplasmic reticulum or out of the cell.
-When Extruded from the cell, it is through Calcium Sodium exchanger (bringing sodium in, which risks causing depolarisation. Consequently, NA K ATPase pumps sodium out and potassium in)
-At toxin concentrations, digoxin blocks Na+ K+ ATPase which results in increased sodium concentrations inside cell, resulting in depolarisation.

Question 30

Explain the phenomenon of recurrent atrial

fibrillation triggered by vagal over activity treated by Disopyramide.

Answer 30

High-frequency stimulation of the vagal nerve affects what’s occurring at the ganglionic plexus at the pulmonary vein, and the subsequent elevated levels of ACh can enhance ectopic beats occurring in that region. This appears to be via effects on potassium currents in cardiomyocytes (not the nodal tissue you’d expect the PNS to be working on). As a result, the action potential is shortened in areas of the atria and can lead to fibrillation due to this localised effect.

Question 31

What are the main differences between the effects of drugs in the 1a, 1b, and 1c classes (graph them and explain) ?

Answer 31

Graphically: refer to slide 4 in extra “Treatment of Dys Annotated” slideshow.

The slope of phase 0 is affected by all three sub-classes, and to different extents based on their degree of blockade of voltage- gated Na channels (a moderate blockage, b weak blockage, c strong blockade).
Also, they have different effects on the effective refractory period (a increases it, b decreases it, c keeps it constant)
The effect on the length of the action potential also varies between sub-classes, which has implications for their use in certain conditions and helps explain why distinction is required.

Question 32

Define “use-dependent”” block.

Answer 32

The degree of block is proportional to the rate of nerve stimulation

Question 33

Define and graph early afterdepolarisation.

Answer 33

For graph, refer to slide 1 in extra slideshow “Treatment of Dys Annotated”

Occur either during phase 2 or phase 3, and more likely to occur in conditions that prolong the QT interval. What ions are responsible depends on the membrane voltage when the event’s triggered: In phase 2 the upstroke is most likely due to Ca2+ channels as all the voltage gated Na channels will be refractory, in phase 3 voltage gated Na channels could most likely cause the upstroke (as more will recover during the repolarisation of the membrane that occurs during phase 3).
This can evoke single or sustained trains of action potentials (refer to same slide).

Question 34

Define and graph delayed afterdepolarisation.

Answer 34

For graph, refer to slide 2 in extra slideshow “Treatment of Dys Annotated”

Occur shortly after repolarisation is complete, usually due to high intracellular calcium concentrations that drive chloride currents or affect the activity of the NCX (sodium-calcium exchanger affected by digoxin) and cause a depolarisation event (see arrowed “hump”). If the magnitude of that “hump” is great enough, then it can breach the threshold required to recruit voltage-gated Na channels and trigger depolarisation.
This can evoke single or sustained trains of action potentials (refer to same slide).